Surveillance of prognostic risk factors in patients with SCCB using artificial intelligence: a retrospective study

Small cell carcinoma of the bladder (SCCB) is a rare urological tumor. The prognosis of SCCB is abysmal. Therefore, this study aimed to construct nomograms that predict overall survival (OS) and cancer-specific survival (CSS) in SCCB patients. Information on patients diagnosed with SCCB during 2004–2018 was obtained from the Surveillance, Epidemiology, and End Results (SEER) database. Univariate and multivariate Cox regression models analyzed Independent risk factors affecting patients' OS and CSS. Nomograms predicting the OS and CSS were constructed based on the multivariate Cox regression model results. The calibration curve verified the accuracy and reliability of the nomograms, the concordance index (C-index), and the area under the curve (AUC). Decision curve analysis (DCA) assessed the potential clinical value. 975 patients were included in the training set (N = 687) and the validation set (N = 288). Multivariate COX regression models showed that age, marital status, AJCC stage, T stage, M stage, surgical approach, chemotherapy, tumor size, and lung metastasis were independent risk factors affecting the patients' OS. However, distant lymph node metastasis instead AJCC stage is the independent risk factor affecting the CSS in the patients. We successfully constructed nomograms that predict the OS and CSS for SCCB patients. The C index of the training set and the validation set of the OS were 0.747 (95% CI 0.725–0.769) and 0.765 (95% CI 0.736–0.794), respectively. The C index of the CSS were 0.749 (95% CI 0.710–0.773) and 0.786 (95% CI 0.755–0.817), respectively, indicating that the predictive models of the nomograms have excellent discriminative power. The calibration curve and the AUC also show good accuracy and discrimination of the nomograms. To sum up, We established nomograms to predict the OS and CSS of SCCB patients. The nomograms have undergone internal cross-validation and show good accuracy and reliability. The DCA shows that the nomograms have an excellent clinical value that can help doctors make clinical-assisted decision-making.


Scientific Reports
| (2023) 13:8727 | https://doi.org/10.1038/s41598-023-35761-w www.nature.com/scientificreports/ Statistical analysis. Continuous variables like age were described using the mean and the standard deviation. Group comparisons were made using the chi-square test or non-parametric U test. Categorical variables such as tumor size, stage, and surgical method were described by frequency and compared using the chi-square test. A Cox regression model analyzed prognostic influencing factors of the patients, and the log-rank test tested the patient survival differences. Statistical analysis was performed using the R software version 4.1.0 and SPSS 26.0. The R packages used included "DynNom", "RMS", "Survival", and "ggDCA". p values less than 0.05 were considered statistically significant.
Informed consent. This study is accordance with relevant guidelines and regulations. All the data in our study were obtained from the SEER database. This is a publicly open database and does not require informed consent from the subjects and/or their legal guardians.

Results
Clinical features. In total, 975 patients were enrolled in this study according to the inclusion-exclusion criteria. The training and validation sets were 687 and 288 cases, respectively. The mean age of the patients was 71.2 ± 11.4 years old, and the patients were predominantly male (75.4%). The patients' race was mostly white, 89.6%, 0.57% married and 43% unmarried. No significant difference in the primary site of the tumor. The Grade grades I-III were 22.5%, grade IV 36%, and grades unknown 41.5%. AJCC stage I was 6.77%, II at 23.9%, III at 8.21%, IV at 25.7%, and AJCC stage was unknown at 35.4%. The T stage was mainly observed in T2, accounting for 51%. The M stage was mainly M0, accounting for 75.7%. N staging is dominated by N0, accounting for 71.6%. The procedure included local tumor excision (63.5%), radical cystectomy (27%), no surgery (9.03%), and unknown (0.51%). The total number of patients receiving chemotherapy was 67.3%. Patients receiving radiotherapy accounted for 28.4%. The tumor size was mainly ≤ 5 cm, accounting for 41.4%. Patients with bone metastases were 7.18%, 9.44% with liver metastases, 4.41% with lung metastases, and 16.9% with distant lymph node metastases. There were no significant differences between the training and validation sets; details are shown in Table 1 Tables 2 and 3.
Development and validation of the nomograms. We developed two new nomograms based on the results of the multivariate COX regression models used to predict patients ' years of OS and CSS (Fig. 2). The nomogram of the OS showed that the tumor size, surgical approach, chemotherapy, distant metastasis, and T stage were the most significant influencing factors for the OS. In addition, marital status and age can also affect  Furthermore, we used internal validation to validate the model's accuracy and discriminability. The C index of the OS in the training set and the validation set were 0.747 (95% CI 0.725-0.769) and 0.765 (95% CI 0.736-0.794, respectively). The C index of the CSS in the training set and the validation set were 0.749 (95% CI 0.710-0.773) and 0.786 (95% CI 0.755-0.817), respectively, which showed that the nomograms of both the OS and CSS have good recognition ability. In addition, the calibration curve shows that the predicted values of the OS and CSS nomogram prediction models are highly consistent with the actual observed values (Fig. 3). The AUC results showed good discriminability of the nomograms, the OS in training set with an AUC of 77.2, 76.0, 75.9 at 1-,3-, and 5 years, respectively. The AUC for OS in the validation was 77.9, 77.1, 74.8, respectively. AUC for CSS in the training set was 76.6, 75.6, 74.8, respectively, and AUC for CSS was 78.3, 77.4, 76.2 in the validation set ( Fig. 4).

Clinical application of the nomograms.
The DCA results showed that the nomograms of both OS and CSS had good clinical value (Fig. 5). And our established OS and CSS nomograms are better than the traditional TNM staging system and the prediction model for SCCB found by Eugene et al. In addition, patients were divided into high-risk groups (total score ≥ 151.6564) and low-risk groups (total score < 151.6564) for CSS, highrisk groups (total score ≥ 151.16284) and low-risk groups(Total score < 151.16284) for OS based on the cutoff value calculated from the ROC curve. The K-M curve showed that the OS and CSS of the high-risk group were significantly lower than those of the low-risk group in both the training and validation sets (Fig. 6). The 1-, 3-, and 5-year survival rates for the high-risk group for OS were 29.45%, 12.19%, and 9.03%, respectively, and the 1-, 3-, and 5-year survival rates for the low-risk group for OS were 73.7%, 47.0%, and 37.4%, respectively. The 1-, 3-, and 5-year survival rates for the high-risk group for CSS were 38.4%, 18.5%, and 16.1%, respectively, and the 1-, 3-, and 5-year survival rates for the low-risk group for CSS were 78.3%, 57.0%, and 48.9%, respectively.In addition, the KM curve also showed that patients with tumor size ≤ 5 cm had the highest OS and CSS rates, and secondly, the lower the T stage, the higher the OS and CSS rates of the patients (Fig. 7). Patients who underwent radical cystectomy had the highest OS and CSS, followed by patients with local tumor excision, and those who received chemotherapy also had higher OS and CSS (Fig. 8). The KM curve also showed that the OS and CSS rates of patients with lung metastases were lower than those without lung metastases, and the survival time of patients with lung metastases did not exceed 24 months; the OS of patients was closely related to the AJCC stage and the lower the AJCC stage was, patients had higher OS; finally, patients with distant lymph node metastases had lower CSS (Fig. 9).

Discussion
Primary SCCB is an extremely rare histological subtype of bladder cancer with extremely low incidence and poor prognosis. Data shows that the median survival time of SCCB patients is 12.7 months 10 . We counted the number of bladder cancer cases and the proportion of SCCB in 2004-2018 from the SEER database. We found that although the incidence of SCCB was still very low, its incidence also increased yearly. Therefore, evaluating the factors affecting the prognosis of patients with SCCB is essential. The nomogram is a tool to assess patients' survival, allowing for the cumulative effects of all prognostic factors to predict the survival probability at 1-,3-, and 5 years 6 . This study used the data from the SEER database to establish two nomograms predicting both OS and CSS in patients with primary SCCB. Our predictive model showed that age, marital status, AJCC stage, T stage, M stage, surgical mode, chemotherapy, tumor size, and lung metastasis were independent risk factors affecting the patients' OS. However, age, marital status, T stage, M stage, surgery, chemotherapy, tumor size, lung metastasis, and distant lymph node metastasis were the independent risk factors affecting the CSS in the patients. Age is associated with the incidence and prognosis of many cancers, and studies have shown that age is an independent risk factor for cancers such as non-small cell lung cancer and breast cancer 11,12 . Previous studies showed that about 90% of bladder cancer patients are over 55 years old, and the average age at diagnosis is 73 years old 13 . The study by Feng et al. showed that younger bladder cancer patients had higher postoperative OS and CSS than older patients 14 . Several studies have reported that older bladder cancer patients have a higher mortality rate than younger patients 15 . Our results showed that the mean onset of SCCB is around 71 years old, similar to the mean age of bladder carcinoma reported by Eugene and Dong et al. 9,16 . Our prediction model showed that age was an independent risk factor for both OS and CSS in patients, with older patients having lower OS and CSS, which is consistent with the prediction model results of Dong et al.
Marital status is considered a prognostic factor in many cancers, and married status is a prognostic protective factor in most cancer patients 17 . Tao et al. found that marital status was an independent prognostic factor for OS in patients with distant metastasis of bladder cancer 18 . Sammon et al. demonstrated that marital status was a risk factor for reduced survival after radical cystectomy and that unmarried conditions impaired the prognosis of bladder cancer patients 19 . Marriage is considered a protective factor for bladder cancer, given that marriage brings patients more financial support and psychological comfort. However, the study by Dong et al. also confirmed that marital status was an independent risk factor for OS but not for CSS in patients with SCCB. Our nomogram shows that being married is a protective factor for OS and CSS in patients with SCCB, considering that the reason may be the increased number of cases.
Previous studies have shown that tumor size is a risk factor for poor prognosis in bladder cancer patients 20 . The study by Lee et al. confirmed that larger tumors in bladder cancer were significantly associated with a shorter time of recurrence 21 . The survey by Karl H Tully et al. confirmed that the smaller the tumor size of nonmuscle-invasive bladder cancer, the higher the progression-free survival and CSS in bladder cancer patients 22 . The nomogram conducted by Tian et al. found that tumor size was an independent risk factor for lymph node metastasis in bladder cancer 23 . The nomogram established by Zhan showed that the tumor size was associated with the CSS prognosis in lymph node-positive bladder cancer patients 24 . Our nomogram and KM curves showed that the smaller the tumor volume of SCCB, the better the patient prognosis, consistent with Dong et al. 9 .
Currently, the treatment of bladder cancer is mainly surgery, radiotherapy, and chemotherapy. However, because the SCCB is very rare, no unified standard scheme exists for its treatment. The study by Carlo Cattrini  26 . However, our nomogram showed a better prognosis for SCCB patients with radical resection, considering that the reason may be that most of the SCCBs are limited to the pelvic cavity so that curative resection can achieve a better therapeutic effect. The KM curve also showed that patients who underwent radical resection had higher OS and CSS. Considering that SCCB is mostly primary cancer, better therapeutic results can be achieved by radical resection. In addition, chemotherapy as an adjuvant therapy remains the primary treatment modality for SCCB patients 27 , and Mackey et al. reported that chemotherapy could significantly improve the prognosis of SCCB patients 28 . The study by Chau et al. found poor overall outcomes for patients with SCCB but improved survival for those who were able to receive chemotherapy 29 . Our KM curve also showed that the chemotherapy patients had a higher OS and CSS, consistent with previous studies. Taking the traditional AJCC staging system as the standard, the AJCC staging system is based on three elements: the T stage reflects the depth of infiltration, the N stage reflects the lymph node state, and the M stage reflects the metastatic state. The nomogram of Yang et al. showed that the lower the T stage, the better the prognosis of bladder cancer patients after radical resection 30 . The N stage represents lymph node metastasis but is confined to the pelvic cavity.However, our study showed that the N stage was not an independent risk factor for OS and CSS in SCCB patients. However, the results of Eugene et al. in 2011 showed that the N stage is an independent risk factor related to the prognosis of SCCB patients 16 . Considering the highly high malignancy of SCCB, the lymph node metastasis confined to the pelvic cavity may not significantly impact its prognosis, and the result may change due to the sample size update.The critical factor affecting the prognosis of bladder cancer patients may be distant metastasis, and the nomogram of Yang et al. confirmed that distant metastasis is an important factor affecting the OS and CSS in bladder cancer patients 31 . Our nomogram also showed that SCCB patients developing distant metastases had worse OS and CSS. At the same time, distant metastases include distant lymph node metastasis and organ metastases. This study separately analyzed bone metastasis, liver metastases, lung metastasis and distant lymph node metastasis.Univariate COX regression analysis showed that both bone metastasis, liver metastasis, lung metastasis and distant lymph node metastasis were essential factors for patient OS and CSS, while the multivariate COX regression model showed that lung metastasis was a common independent risk factor for OS and CSS in SCCB patients, while distant lymph node metastasis was an independent risk factor for CSS in SCCB patients. The KM curve also showed that the patients with lung metastases had a lower OS and CSS and that most patients with lung metastases survived for no more than 24 months. At the same time, patients with SCCB with distant lymph node metastases had a lower CSS. However, the results may be biased due to the small number of organ metastasis cases.
Although the excellent accuracy of the nomogram based on the SEER database was confirmed by internal validation, crucial clinical information related to prognoses, such as smoking and BMI, still needs to be improved, thus some limitations in this study. Secondly, the studies based on the SEER database were retrospective, and selection bias cannot be avoided. Further validation through prospective studies may be required. However, many essential variables were included, so our results were not significantly biased. Moreover, there are very few prediction models for SCCB at present. This study further expanded the sample size based on the prediction model of Dong et al. 9 . Meanwhile, the C index obtained in this study is higher, showing that the accuracy of the prediction model established after expanding the sample size is increased. Meanwhile, we conducted a separate